Bcl-xL deamidation in platelets: mere age marker, or lifespan modulator? – WRINXL

Each year, thousands of platelet concentrates are collected, stored at most 7 days and transfused. The needs for platelets are not met, and extending their shelf-life is a major stake. Therefore, elucidating what regulates platelets lifespan is mandatory.
The WrinXL project has 2 aims: (1) to pinpoint the mechanism of platelet termination, and (2) to screen for new compounds to improve the shelf-life of platelet concentrates.
The consortium is composed of hematologists specialized in platelets, of biochemists specialized in protein aging, and of structural biologists specialized in molecular dynamics. All are experts in the protein Bcl-xL. Together, we found that the protein sustaining platelets survival, Bcl-xL, undergoes sequential deamidation reactions as platelets age. The question we ask is: is this phenomenon just a platelet age marker, or does it cause platelet death?
The deamidation reactions targeting Bcl-xL result from a spontaneous molecular aging which alters the protein composition with so-called "non-natural" amino-acids, i.e. IsoAspartate residues. We hypothesize that these IsoAspartate modify Bcl-xL structure, and impair its survival function. We developed unique tools (2 patent applications filed) and have obtained unique antibodies worldwide, which allow the specific detection of IsoAsp-containing Bcl-xL. We will lead studies from the isolated molecule to whole organisms to investigate the role of Bcl-xL deamidation in platelet viability. A screen will also be performed to isolate new compounds to slow down the molecular aging of Bcl-xL. This project will allow better understanding of how platelets die and will identify better preservative compounds for an improved storage of platelet concentrates. The WrinX project will thus have a significant outreach in public health.